Supplementary Figure from PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

Wanderley, Carlos Wagner S.; Maganin, Alexandre G.M.; Adjafre, Beatriz; Mendes, Atlante S.; Silva, Conceição Elidianne Anibal; Quadros, Andreza Urba; Luiz, João Paulo Mesquita; Silva, Camila Meirelles S.; Silva, Nicole R.; Oliveira, Francisco Fabio Bezerra; Gomes, Francisco Isaac F.; Restrepo, Jeferson Leandro J.; Speck-Hernandez, Cesar A.; Turaça, Fernanda; Silva, Gabriel Victor Lucena; Pigatto, Glauce R.; Nakaya, Helder I.; Mota, Jose Mauricio; Barroso-Sousa, Romualdo; Alves-Filho, José C.; Cunha, Thiago M.; Cunha, Fernando Q.

doi:10.1158/2326-6066.22544931.v1

cir-22-0003_supplementary_figures_suppsf1-sf6.pdf (699.11 kB)

Supplementary Figure from PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

journal contribution

posted on 2023-04-04, 01:40 authored by Carlos Wagner S. Wanderley, Alexandre G.M. Maganin, Beatriz Adjafre, Atlante S. Mendes, Conceição Elidianne Anibal Silva, Andreza Urba Quadros, João Paulo Mesquita Luiz, Camila Meirelles S. Silva, Nicole R. Silva, Francisco Fabio Bezerra Oliveira, Francisco Isaac F. Gomes, Jeferson Leandro J. Restrepo, Cesar A. Speck-Hernandez, Fernanda Turaça, Gabriel Victor Lucena Silva, Glauce R. Pigatto, Helder I. Nakaya, Jose Mauricio Mota, Romualdo Barroso-Sousa, José C. Alves-Filho, Thiago M. Cunha, Fernando Q. Cunha

Supplementary Figure from PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling

Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

History

ARTICLE ABSTRACT

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti–PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.